Apolipoprotein E (ApoE), which maps to 19q13.2, encodes a protein with a role in lipid transport and cholesterol processing. The protein has an N-terminal domain (residues 1-191) containing a low density lipoprotein receptor binding sites, a C-terminal domain (residues 216-299) containing the major lipid binding sites (residues 240-272) and a hinge region between the two domains.
The ApoE gene has three allelic variants: ApoE4, ApoE3, and ApoE2. ApoE3 (also referred to herein as “E4,” E3,” and “E2,” respectively) is the most common form and ApoE2 is the least common. The frequency of the ApoE4 version of the gene in different populations varies, but is always less than 30% and frequently 8%-15%. ApoE4 is known to be a strong risk factor for Alzheimer's disease (AD). The presence of one copy of the allele increases the likelihood of acquiring the disease about threefold and increases the onset of disease an average of 5 years. Two copies of the same allele increases the risk of AD about 8-fold and decreases the age of onset by an average of 10 years. Analysis of autopsies from individuals who have died with AD and have an ApoE4 allele show that Aβ-related pathologies such as plaques and cerebrovascular amyloid is generally increased in those individuals carrying the allele. ApoE as a lipoprotein interacts with lipid particles and hence is involved in lipid transport in plasma, particularly cholesterol. It has been reported to have a role in the maintenance and repair of neurons. The association between ApoE4 and Alzheimer's disease may be mediated by multiple mechanisms both Aβ-dependent and independent. ApoE4 has reported to be associated with increased production and deposition of Aβ and itself to form toxic aggregates and proteolytic fragments (Zhong et al., J. Biol. Chem. 284, 6027-6031 (2009); Mahley et al., PNAS 103, 5644-5651 (2006)).
The E2, E3 and E4 isoforms each has differential capacity to transport lipids and has differential effects on AD with E4 increasing and E2 decreasing the overall risk of AD. The three alleles each differ from one another at only two residues in humans, positions 112 and 158. Apo E2 has a Cys at both sites. E3 has a Cys at 112 and Arg at 158, and E4 has an Arg at both sites. These changes result in overall structural differences in all three isoforms that appear to account for the AD disease-causing propensities.